IntroductionKeratinocytes form a multilayer barrier that protects the skin from invaders or injuries. The barrier function of keratinocytes is in part mediated by the production of inflammatory modulators that promote immune responses and wound healing. Skin commensals and pathogens such as Staphylococcus aureus secrete high amounts of phenol-soluble modulin (PSM) peptides, agonists of formyl-peptide receptor 2 (FPR2). FPR2 is crucial for the recruitment of neutrophils to the sites of infection, and it can influence inflammation. FPR1 and FPR2 are also expressed by keratinocytes but the consequences of FPR activation in skin cells have remained unknown.MethodsSince an inflammatory environment influences S. aureus colonization, e. g. in patients with atopic dermatitis (AD), we hypothesized that interference with FPRs may alter keratinocyte-induced inflammation, proliferation, and bacterial colonization of the skin. To assess this hypothesis, we investigated the effects of FPR activation and inhibition in keratinocytes with respect to chemokine and cytokine release as well as proliferation and skin wound gap closure.ResultsWe observed that FPR activation induces the release of IL-8, IL-1α and promotes keratinocyte proliferation in a FPR-dependent manner. To elucidate the consequence of FPR modulation on skin colonization, we used an AD-simulating S. aureus skin colonization mouse model using wild-type (WT) or Fpr2-/- mice and demonstrate that inflammation enhances the eradication of S. aureus from the skin in a FPR2-dependent way. Consistently, inhibition of FPR2 in the mouse model or in human keratinocytes as well as human skin explants promoted S. aureus colonization.DiscussionOur data indicate that FPR2 ligands promote inflammation and keratinocyte proliferation in a FPR2-dependent manner, which is necessary for eliminating S. aureus during skin colonization.

The human pathogen Staphylococcus aureus is considered mainly an extracellular, opportunistic pathogen, yet the bacterium is able to survive within and escape from host cells, including macrophages. An agr/ sae mutant of strain USA300 is unable to escape from human macrophages but can replicate and survive within macrophages. We questioned whether such “„non-toxic“” S. aureus resembles the less pathogenic coagulase-negative Staphylococcal species (CoNS) like S. carnosus, S. lugdunensis, S. capitis, S. warneri or S. pettenkoferi. We show that in contrast to the “„non-toxic“” S. aureus strains, the CoNS species are efficiently killed within 24 h post-infection in the macrophage-like THP-1 cells or in human primary macrophages. Bacterial persistence of “„non-toxic“” S . aureus or CoNS induced IL-1ß release but no cell-death. Mutations in genes coding for katalase, copprer transport or the regulatory system GraRS or SigB did not impact bacterial survival in THP-1 cells. Deletion of the superoxide dismutases sodA and sodM impaired S. aureus survival in human primary macrophages but not in THP-1 cells. However, expression of the S. aureus specific sodM in S. epidermidis was not sufficient to protect this species from being killed in THP-1 cells. Thus, at least in those cells better bacterial survival of S. aureus could not be linked to higher protection from ROS. However, “„non-toxic“” S. aureus was found to be insensitive to pH, whereas S. epidermidis was protected when phagosomal acidification was inhibited. Thus, species differences seem to be linked to different sensitivity to acidification.